Two nonhuman primate efficacy studies have convincingly demonstrated that wildtype (wt) CMV/SIV vectors can 1) re-infect CMV+ rhesus macaques (RM), 2) during re-infection, elicit potent and persistent SIV-specific CD4+ and CD8+ T cell responses with a strong effector memory (TEM) bias, and 3) completely protect ~50% of vaccinated RM from progressive SIV infection after limiting dose rectal challenge with the highly pathogenic, CCR5-tropic SIVmac239 virus. The protection manifested in these RM is distinct from previous vaccines in its abruptness and extent, with protected RM exhibiting a viral burst in plasma of varying size upon initial infection, followed by immediate control to undetectable levels. Protection correlates with the extent of total SIV-specific CD8+ T cells generated during the vaccine phase, and is stable in the vast majority of protected RM (16/17) for >12 months. These data indicate a novel pattern of protection consistent with very early control, likely taking place at the site of viral entry and/or early sites of viral replication and amplification, and involving tissue-resident CD8+ TEM. Significantly, the epitope targeting of CMV-vectored, SIV-specific CD8+ T cell responses is distinct from responses elicited by conventional viral vectors or SIV itself, excluding the typical immunodominant epitopes that are internally processed in and presented by virally infected cells. This differential epitope targeting of wt CMV vector-elicited CD8+ T cell responses is due to the activity of CMV genes that inhibit class I MHC-restricted Ag presentation (US2-11 homologues), as US2-11 deletant CMV/SIV vectors elicit CD8+ T cell responses that include prominent responses to the conventional (internally processed) SIV epitopes. In this project, we seek to 1) improve the efficacy of CMV vector mediated protection with development of an optimized (epitope matched) heterologous prime for a CMV/SIV vector boost, 2) determine whether US2-11 deletant RhCMV/SIV vectors, which redirect CMV/SIV vector elicited CD8+ TEM responses to typical (directly presented) immunodominant epitopes, have increased efficacy, 3) determine the efficacy of replication-deficient and cell tropism-modified CMV vectors (developed in Projects 1 and 2, respectively), and 4) further define immunologic correlates of the unique protection afforded by CMV-vector elicited immune responses.